In higher eukaryotes, fine-tuned activation of protein-coding genes and many non-coding RNAs pivots around the regulated activity of RNA polymerase II (Pol II). The Integrator complex is the only Pol II-associated large multiprotein complex that is metazoan specific, and has therefore been understudied for years. Integrator comprises at least 14 subunits, which are grouped into distinct functional modules. The phosphodiesterase activity of the core catalytic module is co-transcriptionally directed against several RNA species, including long non-coding RNAs (lncRNAs), U small nuclear RNAs (U snRNAs), PIWI-interacting RNAs (piRNAs), enhancer RNAs and nascent pre-mRNAs. Processing of non-coding RNAs by Integrator is essential for their biogenesis, and at protein-coding genes, Integrator is a key modulator of Pol II promoter-proximal pausing and transcript elongation. Recent studies have identified an Integrator-specific serine/threonine-protein phosphatase 2A (PP2A) module, which targets Pol II and other components of the basal transcription machinery. In this Review, we discuss how the activity of Integrator regulates transcription, RNA processing, chromatin landscape and DNA repair. We also discuss the diverse roles of Integrator in development and tumorigenesis.

在高等真核生物中，蛋白质编码基因和许多非编码 RNA 的微调激活围绕 RNA 聚合酶 II (Pol II) 的调节活性进行。 Integrator 复合物是唯一一种后生动物特异性的 Pol II 相关大型多蛋白复合物，因此多年来一直未被充分研究。 Integrator 至少包含 14 个子单元，这些子单元被分为不同的功能模块。核心催化模块的磷酸二酯酶活性以共转录方式针对多种 RNA 种类，包括长非编码 RNA (lncRNA)、U 小核 RNA (U snRNA)、PIWI 相互作用 RNA (piRNA)、增强子 RNA 和新生前体 RNA。 -mRNA。 Integrator 对非编码 RNA 的加工对于其生物发生至关重要，对于蛋白质编码基因，Integrator 是 Pol II 启动子近端暂停和转录物延伸的关键调节剂。最近的研究发现了 Integrator 特异性丝氨酸/苏氨酸蛋白磷酸酶 2A (PP2A) 模块，该模块针对 Pol II 和基础转录机制的其他组件。在这篇综述中，我们讨论了 Integrator 的活性如何调节转录、RNA 加工、染色质景观和 DNA 修复。我们还讨论了积分器在发育和肿瘤发生中的不同作用。